The overall purpose of this proposal is to determine the level of innate and adaptive immune activation (i.e., anti-viral Th1 cytokines, antibody and cellular immune responses) induced by cationic lipid-DNA (non-coding) complexes (CLDC) combined with whole-inactivated Simian Immunodeficiency Virus (SIV) virions (CLDC-SIVinact) in the Rhesus macaque monkey model. Evidence suggests that CLDC efficiently stimulate the innate and adaptive immune pathways by the presence of CpG and non-CpG motifs as well as other mechanisms yet to be determined. The current formulation of the product is effective at inducing systemic cytokine production as well as substantial humoral and cellular immune responses, particularly cytotoxic T lymphocyte (CTL) activity. The SIV-macaque model was chosen due to its immunological, virological, pathological and clinical similarities to Human Immunodeficiency Virus (HIV) infection in humans. A primary purpose of this proposal is to determine the effectiveness of CLDC adjuvant/immunostimulatory activity, which can subsequently be applied to specific virion, protein or peptide antigens of interest. [unreadable] [unreadable] The specific aims of this proposal are to: (1) characterize the innate immune activation induced in vitro by CLDC-SIVinact on Rhesus monkey PBMC, and (2) compare anti-SIV immune responses (i.e., innate and adaptive) in Rhesus macaques immunized with either CLDC-SIVinact or alum-SIVinact. Immunized monkeys will be analysed for innate immune cytokine responses as well as SIV-specific humoral and cellular immunity (i.e., antibody, T cell proliferation, CTL activity). [unreadable] [unreadable] Positive immunological results from the current study will provide the basis for a subsequent phase II proposal to evaluate the protection afforded by CLDC-SIVinact, in Rhesus macaques challenged with pathogenic SIV. The program will ultimately provide insight and knowledge toward the development of a novel immunostimulant/adjuvant for a prophylactic and/or therapeutic vaccine against HIV infection in humans. [unreadable] [unreadable]